PROJECT SUMMARY/ABSTRACT Narcolepsy is a sleep disorder caused by the selective death of orexin neurons that commonly occurs in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, an abnormal behavioral state between REM sleep and wake. Cataplexy is much more severe in children who develop narcolepsy than in adults, but the underlying mechanisms remain unknown. Histamine is a wake-promoting neuromodulator produced solely in the tuberomammillary nucleus. Histamine neurons are active during cataplexy, possibly maintaining consciousness during this REM sleep-like state. Mice lacking both orexins and histamine exhibit far less cataplexy than mice lacking only orexins, suggesting that histamine is necessary for cataplexy. In children with narcolepsy, cerebrospinal fluid histamine levels are higher than in healthy controls, whereas histamine levels are normal or low in adults with narcolepsy. Our pilot data indicate that orexin neuron loss in mice at age 4 weeks (young-onset) results in very severe cataplexy, whereas orexin neuron loss at age 14 weeks (adult-onset) results in little cataplexy but more REM sleep. We hypothesize that the abundant cataplexy in young mice is caused by a compensatory increase in histamine signaling. We will test this hypothesis by first analyzing sleep-wake behavior in young-onset and adult-onset mice acutely and chronically after orexin neuron loss to confirm that young-onset mice experience more cataplexy. Then, we will use photometry to measure histamine neuron activity during cataplexy and across sleep/wake states in young-onset mice to confirm whether histamine neurons are active during cataplexy. Finally, we will chemogenetically inhibit or activate histamine neurons to test whether elevated histamine neuron activity promotes cataplexy. These experiments will define the role of histamine neurons in the regulation of cataplexy in mice with young-onset or adult-onset orexin neuron loss. Ultimately, elucidating this mechanism of severe cataplexy should enable more targeted treatments for children with narcolepsy.